Clinical and cost-effectiveness of foam sclerotherapy, endovenous laser ablation and surgery for varicose veins: results from the CLASS trial

Treatment options

At that time, the established mainstay of treatment for incompetent varicose veins was surgery in the form of saphenofemoral junction (SFJ) ligation or small saphenous vein (SSV) ligation, stripping and multiple phlebectomies of non-trunk varicosities. Evidence at the time suggested a recurrence rate at 5 years for this kind of conventional surgery of 32% for great saphenous veins (GSVs) and 50% for small saphenous veins. 3

From the time of their introduction around 2000, foam sclerotherapy, endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) had emerged as possible alternative treatment options that could be carried out under local anaesthetic. Foam sclerotherapy, EVLA and RFA aim to reduce the surgical trauma, bruising, scarring and time off work associated with conventional surgery. By 2006, NICE had published interventional procedures guidance on all these procedures, stating that there was adequate evidence on their safety and efficacy for use in the NHS. 11–13 These newer interventions had the potential to increase throughput of varicose vein patients without the need for expensive operating theatre facilities. However, this benefit may be offset by the need for the patient to return for further treatment.

In 2006, there were only two completed RCTs comparing the newer treatments against surgery, both with limited follow-up. One had been published,14 whereas the other, carried out by one of the CLASS co-applicants, had not. 15 These studies are discussed below (see Foam sclerotherapy and Endovenous laser ablation). Critics of the newer procedures pointed to the unknown effect of not treating tributaries at the saphenopopliteal junction and SFJ (an accepted principle of surgery aimed at minimising recurrence) and the need for several treatment sessions compared with ‘one-stop’ surgery.

Despite uncertainty about clinical effectiveness and cost-effectiveness, the use of these newer treatment options was increasing in the UK as alternatives to conventional surgery. A survey in 2006 of members of the Vascular Surgical Society of Great Britain and Ireland and the Venous Forum of the Royal Society of Medicine revealed that the vast majority of surgeons offered conventional surgery to NHS patients, with 27% of surgeons offering foam sclerotherapy, 19% offering EVLA and 3% offering RFA. 16 The following sections describe each of these treatments.

Quality of life

Quality of life was assessed in four of the above studies. In the study by Biemans et al. ,31 there was no difference in QoL [assessed by the disease-specific Chronic Venous Insufficiency Quality of Life Questionnaire (CIVIQ) or the EQ-5D] at 3 months or 1 year. At 3 months, there was no significant difference in AVVQ scores between treatment groups. 32 At 1 year, Rasmussen et al. 29 found significant improvements in the AVVQ and Short Form questionnaire-36 items (SF-36) scores in all treatment groups, but no difference between any of the treatment groups. Similarly, Shadid et al. 33 found no significant difference in the EQ-5D scores between treatment groups at 2 years.

Technical success

This was assessed in all six studies at various time points up to 2 years. At 1 year, the occlusion rate for foam sclerotherapy (73%) was significantly lower than for either surgery (88%, p < 0.02) or EVLA (89%, p < 0.02). 31 At 3 months, the technical success rate was found to be similar for foam sclerotherapy and EVLA (above-knee GSV occlusion rate 69% vs. 74%, p = 0.596). 32 At 6 months, Figueiredo et al. 30 found no statistically significant difference in technical success between patients randomised to foam sclerotherapy and those randomised to surgery (vein obliteration in 90% vs. 78%).

In the study by Wright et al. ,14 the technical success at 12 months was slightly higher in the surgery group (86%) than in the Varisolve^® group (84%), but this did not reach statistical significance. Rasmussen et al. 29 found that the technical success rates at 12 months were significantly lower in patients receiving foam (84%) than in those receiving EVLA (94%), RFA (95%) and surgery (97%) (χ² p < 0.001).

Return to normal activities

This was reported in three of the five studies. Wright et al. 14 found that the time to return to normal activities following treatment was shorter in the foam sclerotherapy group than in the surgical group (median 2 vs. 13 days, p < 0.001). In the study by Rasmussen et al. ,29 the median time to return to normal activities was shorter in the patients in the foam sclerotherapy and RFA groups (1 day in each) than in the EVLA (2 days) and surgery (4 days) groups (p < 0.001). The study by Lattimer et al. 32 found that the mean time to return to normal activities was shorter following foam (3 days) than EVLA (7.5 days) (p = 0.11).

Venous Clinical Severity Scores

The VCSSs were assessed in three studies, and improved significantly after the procedure in all groups, with no differences noted between groups. 29,30,32

Clinical, etiological, anatomical, pathological classification

One study considered the clinical, etiological, anatomical, pathological (CEAP) classification. 31 Although the CEAP classification improved after foam sclerotherapy, EVLA and surgery, there was no difference between groups at 3 or 12 months.

Clinical recurrence rates

In the study by Rasmussen et al. ,29 the 1-year clinical recurrence rates in those randomised to foam, surgery, EVLA and RFA were similar (14%, 15%, 12% and 7% respectively, p = 0.155).

A further study defined clinical recurrence in terms of a combined end point of reflux combined with venous symptoms at 2 years. 33 This end point was found to occur equally in patients randomised to foam sclerotherapy (11%) or surgery (9%) (p = 0.407).

Costs

These were reported in three of the studies, with all three reporting that foam was the least costly option. Lattimer et al. 32 calculated the cost of foam sclerotherapy to be approximately one-third of the cost of EVLA. In the study by Shadid et al. ,33 hospital costs over a 2-year period in patients receiving foam sclerotherapy were less than half of those in the surgery group. Rasmussen et al. 29 found that foam sclerotherapy was the cheapest option, and that EVLA and surgery were more expensive.

Quality of life

Eight studies reported QoL, using instruments which included the AVVQ, SF-36, EQ-5D and the disease-specific CIVIQ. In all of these studies, no significant difference was noted in patients randomised to EVLA or surgery at various follow-up time points ranging from 3 months to 5 years. 15,29,31,34,35,37,38,50,51 Disease-specific QoL was found to be reduced in patients who developed a clinical recurrence compared with those who did not (p = 0.001). 35 In this study, the clinical recurrence rates were lower in patients who received EVLA than in those who underwent surgery at 1-year follow-up (p < 0.001). 35

Technical success

This was assessed in all 10 of the studies at various time points. In the study by Flessenkamper et al. , technical success (no inguinal venous reflux) was achieved after 2 months in 92% of the EVLA group, 98% of the EVLA/high-tie group and 100% of the standard surgery group. 37,39 Darwood et al. 15 found that, at 3-months follow-up, abolition of reflux was achieved in 94% of EVLA and 88% of surgical patients (p = 0.227), and that, by 1 year, technical success had reduced in both groups. At 6 months, Rasmussen et al. 36 reported no significant difference in technical success at 1 year (94% in the EVLA group and 98% in the surgery group, p > 0.05). In the later study by Rasmussen et al. ,29 technical success was 94% following EVLA compared with 96% following surgery (p = 0.543). Biemans et al. 31 found no difference in anatomical success following EVLA (89%) or surgery (88%).

In the study by Carradice et al. ,35 the technical success rate at 6 weeks was slightly lower in patients randomised to surgery (92%) than in those who underwent EVLA (99%) (p = 0.005). In the study by Pronk et al. ,40 the technical success was similar in both surgery (90%) and EVLA (91%) groups at 1 year.

In the study by Christenson,34 initial technical success (no detectable reflux at 12 days) was 99% in the EVLA group and 100% in the surgery group. The one study involving patients undergoing treatment to the SSV system found that the technical success (abolition of reflux) was greater in the EVLA group (96%) than in the surgery group (72%) at 6 weeks (p < 0.001). 37

Return to normal activities

In the study by Darwood,15 patients randomised to EVLA had a quicker return to normal activities and work than those randomised to surgery (p = 0.001 and p = 0.005 respectively). Similarly, Rass et al. 38 found that patients having EVLA returned to work more quickly than those having surgery; this was despite there being no difference in return to basic physical activities between the groups. Pronk et al. 40 found that recovery (mobility, self-care and daily activities) was better in patients randomised to surgery than in those randomised to EVLA at day 7 (p < 0.05); however, there was no difference in the mean number of days taken to restart daily activities, work and sport between the groups. In two studies by Rasmussen et al. ,29,36 there was no difference in return to normal activities and work between patients randomised to EVLA and surgery. In the one study to involve patients undergoing SSV treatment,37 patients who had EVLA returned to normal activities and work earlier than those undergoing surgery (p < 0.001).

Venous Clinical Severity Score

The VCSS was assessed in six studies, and scores improved significantly after treatment in all groups, with no differences noted between treatment groups. 15,29,34,37,49,51 In the study by Rass et al. ,38 an alternative assessment tool (the Homburg Varicose Vein Severity Score) was used; again there was no difference between treatment groups.

Clinical, etiological, anatomical, pathological classification

Three studies considered CEAP as an outcome measure. There was no difference in CEAP between intervention groups at 2 months39 and 1 year31,40 in patients undergoing EVLA versus surgery.

Clinical recurrence rates

These were reported in five studies. The clinical recurrence rates at 1 year, in the study by Pronk et al. ,40 were approximately 10% in both the EVLA and surgery groups. In contrast, Carradice et al. 35 found the clinical recurrence rate at 1 year to be lower after EVLA (4%) than after surgery (20%) (p < 0.001).

Rass et al. 38 reported recurrent varicose veins on clinical examination in 16.2% of the EVLA group versus 23.1% of the surgery group at 2 years (p = 0.15). Higher 2-year clinical recurrence rates were reported by Rasmussen et al. 49 (surgery 37%, EVLA 26%). In the 5-year results from this study, there was no difference in recurrence rates (surgery 55%, EVLA 47%, p = 0.72). 51 In the study by Rasmussen et al. 29 where four different treatment options were compared, clinical recurrence rates at 1 year were reported as 14% following foam, 15% following surgery, 12% following EVLA and 7% following RFA (p = 0.155).

Costs

In addition to the Rasmussen study,29 which was discussed previously, the group has reported another study which assessed the costs of EVLA versus surgery. 36 In both studies, the procedure-related costs were higher for EVLA than for surgery.

Participants

Recruitment process

In trial centres where potentially eligible patients could be identified in advance of their attendance at an outpatient clinic, the postal summary information sheet (see Appendix 1, which contains all study paperwork, case report forms and questionnaires) was sent to them in advance of their appointment. Patients who were identified at an outpatient clinic were provided with the summary information sheet at the clinic (see Appendix 1).

The surgeon informed potentially eligible patients about the CLASS study, the different treatments available and the risks and benefits of the treatment options. The surgeon also provided patients with a study information leaflet, and an information leaflet providing detailed information about the alternative methods of treatment.

In some centres, the duplex scan was undertaken during this initial consultation; in such cases, only those patients who were eligible on the basis of the results of this scan were informed about the study.

All patients attending an outpatient clinic were logged on the study clinic log. If the patient was potentially interested in the study, his or her contact details were noted on the study clinic log. For patients who were not eligible for the study, or who were not interested in taking part, we recorded the reason for this on the study clinic log.

Around 1 week after the initial consultation, the research nurse telephoned patients who had indicated that they were potentially interested in taking part in the trial to ascertain whether or not this was still the case. If the patient was interested in taking part in the study, he or she was invited to a recruitment appointment at the clinic to provide informed consent. If the patient did not undergo duplex scanning at the initial consultation, this was undertaken at the recruitment appointment. Participants were asked to complete a baseline questionnaire. The baseline case report form was also completed at this appointment.

In participants who presented with bilateral varicose veins, the more severely affected leg (as determined by the participant) was nominated as the study leg. Where possible, the other leg was treated using the same treatment modality as the study leg, either at the same time as the study leg was treated, or sometime thereafter.

In some circumstances (for example, where the duplex scan was completed at the initial consultation and the patient lived a considerable distance from the recruitment clinic, or it was difficult for him or her to attend a recruitment clinic), the consent form and baseline questionnaire were sent to the participant, who was asked to complete these and return them by post. In these circumstances, the research nurse was available, by telephone, to answer any questions about the study.

If patients wanted to consent to the study at their initial outpatient appointment, this was also permitted.

Randomisation and allocation to intervention

Participants were randomised using a computer-generated randomisation system managed by the Centre for Healthcare Randomised Trials (CHaRT) at the University of Aberdeen. This was available to sites as a web-based or telephone system.

In the eight recruitment sites which offered all three interventions (stratum A), participants were randomly allocated 1 : 1 : 1 to EVLA, foam sclerotherapy or surgery using treatment allocation by minimisation. In the three sites which offered only two of the interventions (stratum B), participants were randomly allocated 1 : 1 to foam sclerotherapy or surgery. Each of these two strata (based on treatment options available at the trial centre) had its own separate treatment allocation application. For each application, the minimisation algorithm included centre, age (< 50 years, ≥ 50 years), sex, presence of GSV or SSV, and unilateral or bilateral veins.

After randomisation, participants were placed on the appropriate waiting list. The aim was to keep participants blinded to their treatment allocation until around 2 weeks prior to their treatment. Around 2 weeks prior to treatment, an appointment for treatment was issued by the hospital; at this time the trial office also informed the participant of his or her randomisation. However, at some sites, local processes meant that participants were informed of their randomisation by site staff in advance of this. The delay in informing participants about their treatment allocation was an attempt to minimise the possibility of unequal dropout between the arms.

A letter was sent to the participant’s general practitioner (GP) at trial entry to inform them that their patient had agreed to participate in the trial. Around the time that the participant was informed of his or her treatment allocation, a second letter was sent to the GP informing them of the allocation.

Trial interventions

Measurement of secondary outcomes

Recruitment appointment (baseline, before randomisation)

The disease-specific and generic QoL instruments (AVVQ, EQ-5D and SF-36) and the Illness Perception Questionnaire – Revised (IPQ-R)63 were combined into a single questionnaire for the participant to complete. Participants were asked to complete this questionnaire at baseline (at the recruitment visit). Participants could opt to complete this at home, and if they did not return this within 3 weeks, they were sent a reminder letter, a further copy of the questionnaire and a reply paid envelope. Early on in the recruitment phase, the randomisation system was amended such that participants could not be randomised until the questionnaire had been completed.

Participants were asked to rate their varicose veins on a VAS (from ‘no varicose veins’ to ‘the worst varicose veins I can imagine’). Independently, the research nurse also completed an identical VAS.

The baseline clinical form – incorporating CEAP and VCSS for both legs, duplex scan information and vein involvement in relation to the study leg, as well as some demographic information including height, weight, employment status, previous treatment and previous DVT – was also completed at the recruitment appointment.

Personal details, including GP details and a ‘best contact’, were also collected at recruitment. Participants were asked to nominate a best contact, ideally someone who did not live at the same address as them, who could be contacted if contact with the participant was lost.

After randomisation, before treatment

The pre-treatment questionnaire included the IPQ-R. Approximately 2 weeks before the treatment appointment, the questionnaire was sent to the participant, along with a reply paid envelope. Participants were asked to complete and return this before they attended for treatment. In view of the time frame for completion, reminder letters were not sent for this questionnaire. In some circumstances (e.g. when the treatment date was added retrospectively to the trial database, or immediately before the treatment appointment), it was not appropriate to send the questionnaire as it could not be completed before the treatment appointment.

Treatment appointment

A treatment-specific case report form (CRF) was completed by the treating surgeon (or delegate) after each treatment appointment. The information collected included information specific to the procedure, the grade of surgeon (and, if appropriate, the anaesthetist), how long the procedure took, details of the bandaging, any immediate complications associated with the treatment, whether or not the patient was hospitalised after the treatment and whether or not the contralateral leg was treated contemporaneously. If the participant was undergoing treatment other than the treatment to which he or she had been randomised, the CRF captured this information, together with information about the actual treatment received.

After bandaging, participants were asked to rate the pain experienced during treatment on a VAS ranging from no pain to the worst imaginable pain.

Six-weeks follow-up appointment

Participants were invited to attend for a 6-weeks follow-up appointment. At the appointment, the research nurse carried out a clinical examination of the study leg and completed a CRF incorporating the VCSS and CEAP. The technical success of the treatment was assessed by duplex scanning, performed by an independent, fully trained technician as described above.

Information about any complications or side effects was also recorded. The research nurse and participant assessed the presence of varicose veins using a VAS (ranging from ‘no varicose veins’ to ‘the worst varicose veins I can imagine’).

Participants treated with EVLA or foam sclerotherapy were assessed for further foam sclerotherapy treatment. In some cases this was carried out at the 6-weeks appointment; in other cases the participant returned to the clinic at a later date for this.

As at baseline, the disease-specific and generic QoL instruments (AVVQ, EQ-5D, SF-36) were combined into a single questionnaire for completion by the participant. The Behavioural Recovery After treatment for Varicose Veins (BRAVVO) instrument relating to behavioural recovery, including time to return to work/normal activities, was also included in this questionnaire (the development of this instrument is described in Chapter 8). Two questions on pain were also included. Participants were asked to rate, on a VAS ranging from no pain to the worst imaginable pain, the worst pain experienced while (1) having the treatment and (2) recovering after treatment.

Participants who opted to take the questionnaire home were provided with a reply paid envelope for its return. Participants who failed to return their questionnaire within 3 weeks were sent a reminder letter, a further copy of the questionnaire and a reply paid envelope. Participants who failed to attend for a follow-up appointment were offered a second appointment. If they failed to attend this, they were sent the questionnaire, covering letter and a reply paid envelope for its return. Again, those who failed to return their questionnaire within 3 weeks were sent a reminder letter, a further copy of the questionnaire and a reply paid envelope.

Six-months follow-up appointment

The 6-months follow-up took a similar form to the 6-weeks follow-up. Participants were invited to attend for a 6-months follow-up appointment. At the appointment, the research nurse carried out a clinical examination of the study leg and completed a CRF incorporating the VCSS and CEAP. The technical success of the treatment was assessed by duplex scanning (as described for the 6-weeks follow-up). Where possible, an individual patient was scanned by the same technician at each time point using the study designated duplex scanner. Information about complications and side effects of treatment was also recorded. The presence of varicose veins was assessed by both the participant and the research nurse using a VAS (as previously described). The research nurse also reviewed the hospital medical records to collect information on any hospital appointments or admissions.

The disease-specific and generic QoL instruments (AVVQ, EQ-5D, SF-36) and the IPQ-R were again combined into a single questionnaire for the participant to complete. Questions relating to resource use (primary and secondary care services), self-purchased health care, and participant time and travel costs were included in the 6-months questionnaire only (for more details see Chapter 9). Participants could opt to complete the questionnaire at home; the same reminder schedule was used as for the 6-weeks questionnaire. Participants who failed to attend for the 6-months appointment were offered a second appointment and, if they failed to attend this, a copy of the questionnaire was sent to them, along with a covering letter and a reply paid envelope, with a reminder 3 weeks later.

Data management

A secure, bespoke study database was developed which site staff could access over the internet. Password-protected access was provided such that sites could only view data from their own site. All data collected during the course of the research were kept strictly confidential and accessed only by members of the trial team. Patients’ details were stored under the guidelines of the 1988 Data Protection Act. 64 Patients were allocated an individual study number, and this number (rather than the participant’s name) was used to identify study paperwork.

Clinical data were entered into the database by the research nurse working in each hospital site, together with data from questionnaires completed at clinic. Data from questionnaires returned by post to the study office were entered by staff based there.

Staff in the study office worked closely with local research nurses to ensure that the data were as complete and accurate as possible. Extensive range and consistency checks further enhanced the quality of the data.

Foam versus surgery

For this primary comparison, strata A and B can be combined without introducing any bias. A trial with 385 patients in each group (total 770 patients) will have at least 90% power at a 5% significance level to detect a change of 0.25 SDs in both AVVQ and EQ-5D. Adjusting for baseline score allows the sample size to be decreased by a factor of 1 − correlation squared, so including 385 participants allows for a 10% loss to follow-up at 6 months (assuming a correlation between baseline and 6-months scores of at least 0.31). A correlation of 0.31 is, in our experience, conservative for QoL studies, but should the loss to follow-up be 15%, the study would still have 90% power to detect a difference of 0.25 SDs. Cost savings will be sensitive to the number of participants with recurrent varicose veins requiring reintervention in each group. Allowing for additional loss to follow-up (up to 20%) by 5 years, the study will have 90% power to detect a 15% difference in recurrence from 32% in conventional surgery to 45% in the other groups (which would be funded separately).

Endovenous laser ablation versus surgery

For this primary comparison, only participants in stratum A provide a direct randomised comparison, giving 245 participants in each group (490 in total). This trial will have 80% power at 5% significance to detect a difference of 0.25 SDs. Given adjustment for baseline measures, this allows for a 10% loss to follow-up.

Recruitment to the trial was lower than anticipated for a number of reasons. These included a lower-than-anticipated proportion of varicose vein referrals who met the eligibility criteria, ‘rationing’ of varicose vein treatment at some sites leading to a sharp decline in the number of patients being referred for treatment, and a lower-than-anticipated proportion of eligible patients agreeing to take part. Additional recruitment sites were sought in an attempt to compensate for the recruitment shortfall, but few UK sites offered the appropriate treatment options to enable them to participate in the study. Despite some additional sites, and an extension to the recruitment period, the original recruitment targets were not met. Thus, the DMC and TSC were asked to consider a revised recruitment target of 779 (Table 5).

We provided the following justification for this request. The correlation, pooled across trial arms, between the AVVQ at baseline and 6 months post surgery was 0.39, and this has the effect of providing greater power than originally assumed. In the surgery versus foam comparison, the power achieved with the sample size of 283 in each arm would be equivalent to 334 in each arm if no correlation was observed. Similarly, the power achieved with the sample size of 211 in each arm of the surgery versus EVLA comparison would be equivalent to 249 in each arm if no correlation was observed.

However, at 6 months the response to follow-up was 89%, 1% of questionnaires did not include sufficient data to derive a valid AVVQ and the proportion of participants withdrawn (including those withdrawn prior to receiving an intervention) was 7%. Together, these factors indicated that a valid AVVQ could be expected in 82% of the planned sample.

Therefore, the sample size was effectively 275 (i.e. 82% of 334 in each arm of the surgery vs. foam comparison) for the purpose of determining power (Table 6).

Similarly, the sample size was effectively 205 in each arm of the surgery versus EVLA comparison (Table 7).

Note that although the proposed revised trial sample size was decreased, there was no change to the target differences assumed to be clinically important (0.25 SDs); the only amendment to the sample size calculation was a decrease in the power of the study to detect a 0.25-SD change. Both the DMC and TSC agreed this amendment.

The Aberdeen Varicose Vein Questionnaire

The AVVQ consists of 19 items (a diagram at the beginning on which respondents mark the location and extent of their varicose veins, followed by 12 ordinal response items, of which six require separate responses for each leg). The outcome measure is scored from 0 to 100 (higher values indicate worse QoL), and scores were calculated using weightings for each response in the questionnaire. Where a response was omitted by the respondent, the score for that item was removed from the denominator so that participants could still score between 0 and 100 even if the questionnaire was not fully completed. 59 If the participant had unilateral disease at the time of completing the questionnaire (determined from the veins drawn on the diagram), then, for unanswered questions which related to the healthy leg only, it was assumed that the response should be ‘no’ or ‘none at all’ and a value of 1 was imputed. Once this was executed, any questionnaires with more missing responses than non-missing responses (i.e. 10 missing items or more) were considered not to have valid scores.

The Venous Clinical Severity Score

The VCSS consists of 10 ordinal response items, each with four levels (coded from 0 to 3). The overall score was calculated as the sum of the values across each of the 10 responses, so that a VCSS score could potentially be in the range from 0 to 30 (higher scores indicate greater severity). If the response to question 7 was ‘no active ulcers’ and the responses to questions 8 and 9 (relating to active ulcers) were missing, then questions 8 and 9 were assigned a value of zero. For other missing items, if the equivalent response was available from the AVVQ then these missing responses were assigned the appropriate value. A valid VCSS was not obtainable for participants for whom there remained any missing responses.

Background

As it was not possible for participants to be blinded to their treatment, several steps were taken to increase our confidence in the trial results based on the primary QoL outcomes. As much as possible, information provided to participants at recruitment, after randomisation and following treatment was standardised.

We also conducted a theory-based process evaluation to identify possible confounding variables, for example, expectations or concerns that might differ between treatment groups after participants were informed of the treatment they would receive and that might, in turn, influence recovery behaviours or QoL. The theoretical basis for this process evaluation was the common-sense self-regulation model (CS-SRM). 68

The CS-SRM proposes that people respond to a potential health threat in terms of their perceptions, beliefs and expectations (‘cognitive’ representations) and also in terms of anxieties and concerns (‘emotional’ representations). People use a range of coping behaviours (e.g. self-medicating, seeking social support or perhaps avoidance) to manage and regulate these representations. Systematic review evidence suggests that illness representations play a significant role in help-seeking behaviour and adherence to treatment recommendations. 69,70

Questionnaire measures have been developed and validated to assess the proposed domains of illness representations. The domains are illness identity; causes; timeline; consequences; control; coherence; and emotion. Table 8 presents the label, a brief explanation and an example questionnaire item for each of the domains of the illness perceptions framework.

Methods

The most frequently used, validated scale to assess illness representations is the IPQ-R. 63 The IPQ-R assesses each of the domains in the illness perceptions framework. This questionnaire was administered to trial participants at baseline, following randomisation and 6 months after treatment.

We were particularly interested in whether or not participants in any of the trial arms reported different illness perceptions after they were notified of the treatment to which they had been randomised (but before treatment). We were also interested in whether or not illness perceptions improved following treatment, particularly with regard to the domain of treatment control, as this would likely reflect participants’ perceptions of the effectiveness of their treatment, and timeline and consequences, as these would likely reflect the extent to which participants’ expectations were exceeded following treatment.

Analysis

Quality of life

A valid AVVQ score (our primary outcome) was obtained for all but one of the participants who completed a baseline questionnaire, and the mean score was 17.9 (SD 9.5) (Table 12). The mean EQ-5D was 0.79 (SD 0.18).

For SF-36, the mean physical component score of 48.6 (SD 8.3) was lower than the mean mental component score of 51.8 (SD 9.2) and the population norm score for the physical component of 50 (SD 10). This indicates that, compared with the wider population, the study cohort had slightly poorer physical health at baseline and the low SDs suggest that the cohort was a relatively uniform group in terms of QoL. The main factor contributing to the lower physical component score was the bodily pain domain, with a subscale score of 47.3 (SD 8.9).

Physical activity

A summary of physical activity data collected at the baseline clinic assessment is presented in Table 13. Thirteen per cent of participants spent most of their time at work sitting (e.g. in an office) and 31% spent most of their time at work standing or walking without requiring much intense physical effort. Twenty-four per cent worked in jobs involving definite physical effort, including handling heavy objects and using tools, and 6% had employment involving vigorous physical activity including handling very heavy objects.

In the week prior to recruitment, 45% of participants engaged in physical exercise such as swimming, jogging, aerobics, football, tennis and gym workouts (including 21% who had exercised for more than 3 hours).

Baseline characteristics of study leg

The majority of participants (653/785, 83%) had GSV reflux only, 56 (7%) had SSV reflux only and the remaining 76 (10%) had both GSV and SSV involvement (Table 14). The proportions of participants with left or right leg involvement were similar. The mean widest diameter below the SFJ was 8.7 mm for those with GSV involvement only, and for those with SSV involvement only, the mean widest diameter below the saphenopopliteal junction was 7.5 mm. Of those with any GSV involvement, 90% had reflux above the knee only. All participants had a CEAP classification of C2 or above (reflecting the inclusion criteria for the trial), and 55% had grade C2 veins. The mean VCSS at baseline was 5.0 (SD 2.5). The severity of varicose veins, assessed on a VAS from 0 (none) to 10 (worst possible), recorded higher scores (i.e. a perception of more varicose veins) when assessed by the participant (mean score 5.5, SD 2.2) than when assessed by the research nurse (mean score 3.8, SD 2.2).

Contralateral leg

The baseline CEAP classification and VCSSs are summarised in Table 15 for the 28% of participants with bilateral disease. The majority of these participants (63%) had a C2 CEAP classification for their contralateral leg; the distribution of CEAP classifications was similar for study legs and contralateral legs. The mean VCSS for contralateral legs was 3.8 (SD 2.3), which was lower than the mean score of 5.0 for the study legs.

Results from the foam sclerotherapy versus surgery comparison, which included patients from all centres (n = 575), are described in Chapter 5. Results from the foam versus EVLA and EVLA versus surgery comparisons, which included patients in the centres which participated in the three arms (n = 630), are described in Chapter 6.

Baseline characteristics

Procedure and treatment time

At the time of the primary intervention, more participants in the surgery arm had treatment to non-truncal varicosities (90%) than in the foam arm (31%) (see Table 21). More patients in the surgery arm (15%) had their contralateral leg treated at the same time than in the foam arm (3%).

The mean treatment duration (the time taken from preparation of the patient to completion of bandaging) was longer for surgery (53 minutes, SD 22.9 minutes) than for foam (19 minutes, SD 10.6 minutes). Foam sclerotherapy was performed by consultants much more often (77% of treatments) than surgery (59%). Only 8% of foam participants received treatment from a trainee, compared with 32% in the surgery group. The remainder of procedures were performed by staff grades or nurse consultants. Nearly all patients (98%) randomised to surgery had a general anaesthetic, with six receiving an epidural/spinal anaesthetic (Table 22). The anaesthetist was a consultant in 83% of cases.

Primary treatment volume of foam

The total mean volume of foam administered was 9.0 ml (SD 2.9 ml). When the GSV alone was treated, the mean volume was 9.2 ml (SD 2.9 ml), with 8 ml (SD 3.0 ml) to the truncal vein and 1.2 ml (SD 2.2 ml) to the truncal varicosities (Table 23). There were six patients who received foam in excess of the 12-ml limit recommended in the protocol, without adverse consequences.

Secondary or tertiary foam treatments

The numbers of participants who received secondary or tertiary treatments of foam sclerotherapy, along with a breakdown of the location of treatment, is shown in Table 24. Seventeen participants randomised to foam sclerotherapy (7%) received additional foam treatment to non-truncal varicosities, compared with one randomised to surgery (1%). There were two participants whose second foam treatment included foam sclerotherapy to the GSV and also to non-truncal varicosities. The one participant who received a tertiary treatment had treatment to both the SSV and GSV.

Bandaging/compression

All participants had a bandage or stocking applied to their study leg, nearly all of which were full length. More foam participants (38%) than surgery participants (11%) received bandaging not according to protocol (see Table 21). The main reason for this difference was that the protocol specified the brand of bandaging/compression for patients undergoing foam sclerotherapy, whereas, for surgery, any type of bandaging for 10 days was sufficient. Of the 103 cases of foam participants whose bandaging was not according to protocol, only 10 were related to duration and the other 93 were related to the type of stockings.

Aberdeen Varicose Vein Questionnaire

At 6 weeks and 6 months, all QoL measures showed an apparent improvement compared with baseline. The treatment effect estimate for AVVQ (our primary outcome) at 6 weeks was −2.26 (95% CI −3.67 to −0.86, p = 0.002) in favour of surgery and at 6 months the estimate was −1.74 (95% CI −2.97 to −0.50, p = 0.006).

Sensitivity analyses

There were some missing AVVQ scores at 6 months (26% for the surgery arm and 17% for foam). Exploratory analysis shows that participants without a valid AVVQ score at 6 months had mean baseline AVVQ scores of 18.3 (SD 11.4) for foam and 18.2 (SD 10.3) for surgery. Those with an AVVQ score at 6 months had mean baseline scores of 17.4 (SD 9.7) for foam and 18.2 (SD 8.8) for surgery, indicating that there are differences in the missing data between groups. The mean AVVQ score at 6 weeks for participants with missing scores at 6 months is 11.8 for foam (slightly lower than the mean for all foam participants) and 7.7 for surgery (much lower than the mean for all surgery participants), which suggests that the treatment effect of −1.74 in favour of surgery may be underestimated in the primary analysis.

Table 28 demonstrates different estimates of the effect of treatment on the primary outcome when all missing AVVQ scores at 6 months have been imputed under varying assumptions. Under the ‘missing not at random’ assumption, the estimate of treatment effect is −2.00 (95% CI −3.30 to −0.70). Variously adding or subtracting two points to or from these imputed values, for either one arm at a time or both arms simultaneously, the resulting estimates range from −1.47 to −2.52, all significantly in favour of surgery. The missing AVVQ values for surgery would need to be at least 2.7 points higher (or the missing values for foam 4.0 points lower) than the imputed values for the difference between the groups to be non-significant.

Short Form questionnaire-36 items

There were no differences between foam and surgery for the overall physical and mental component scores or individual domains of the SF-36.

European Quality of Life-5 Dimensions

There were no differences in the EQ-5D or EQ-5D VAS between the foam and surgery groups.

Clinical outcomes

Procedural complications

The event rate for any complication was similar in both groups (6% for foam and 7% for surgery) (Table 35). Six participants in the foam group (2%) and three in the surgery group (1%) each experienced two complications. In patients randomised to surgery, 2.5% had an unscheduled overnight admission following their treatment (see Table 21).

Later complications

Complications recorded at the time of the 6-week and 6-month assessments are shown in Tables 36 and 37. Estimates of the effect of treatment on complications are summarised across both follow-up time points in Table 38, with ORs comparing surgery with foam sclerotherapy. The overall complication rate was lower for surgery than for foam sclerotherapy at 6 weeks (OR 0.40, 95% CI 0.26 to 0.62; p < 0.001) and at 6 months (OR 0.64, 95% CI 0.44 to 0.92; p = 0.015).

The event rates for cutaneous numbness (6 weeks OR 3.98, 95% CI 2.11 to 7.50; p < 0.001, and 6 months OR 5.39, 95% CI 2.50 to 11.62; p < 0.001) were significantly higher for surgery than for foam sclerotherapy. Wound infection occurred in 9.2% of the surgical patients at 6 weeks – a much higher proportion than the 0.8% of foam patients with wound infection – but clearly this complication only occurred in foam patients who had treatment other than that to which they had been randomised.

However, the rates for lumpiness (6 weeks OR 0.23, 95% CI 0.15 to 0.34; p < 0.001, and 6 months OR 0.18, 95% CI 0.10 to 0.33; p < 0.001), skin staining (6 weeks OR 0.12, 95% CI 0.07 to 0.21; p < 0.001, and 6 months OR 0.16, 95% CI 0.10 to 0.28; p < 0.001), persistent tenderness (6 weeks OR 0.52, 95% CI 0.36 to 0.77; p = 0.001) and headache (6 weeks OR 0.31, 95% CI 0.10 to 0.98; p = 0.047) were all significantly higher for foam sclerotherapy than for surgery. There were no differences for persistent bruising, skin loss/ulceration or development of thread vein at either time point. There was also no difference for backache at 6 weeks. At 6 months, data on wound infection, persistent tenderness, backache and headache were not collected.

Baseline characteristics